Masaya Okada1, Jun Imagawa2, Hideo Tanaka3, Hirohisa Nakamae4, Masayuki Hino4, Kazunori Murai5, Yoji Ishida5, Takashi Kumagai6, Seiichi Sato7, Kazuteru Ohashi8, Hisashi Sakamaki8, Hisashi Wakita9, Nobuhiko Uoshima10, Yasunori Nakagawa11, Yosuke Minami12, Masahiro Ogasawara13, Tomoharu Takeoka14, Hiroshi Akasaka15, Takahiko Utsumi16, Naokuni Uike17, Tsutomu Sato18, Sachiko Ando19, Kensuke Usuki20, Syuichi Mizuta21, Satoshi Hashino22, Tetsuhiko Nomura23, Masato Shikami24, Hisashi Fukutani25, Yokiko Ohe26, Hiroshi Kosugi27, Hirohiko Shibayama28, Yasuhiro Maeda29, Toshihiro Fukushima30, Hirohito Yamazaki31, Kazuo Tsubaki32, Toshimasa Kukita33, Yoko Adachi34, Toshiki Nataduka35, Hiroto Sakoda36, Hisayuki Yokoyama37, Takahiro Okamoto38, Yukari Shirasugi39, Yasushi Onishi40, Masaharu Nohgawa41, Satoshi Yoshihara42, Satoshi Morita43, Junichi Sakamoto44, Shinya Kimura45. 1. Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan. 2. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan. 3. Department of Hematology, Hiroshima City Asa Hospital, Hiroshima, Japan. 4. Department of Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan. 5. Department of Hematology and Oncology, Iwate Medical University, Morioka, Japan. 6. Department of Hematology, Ohme Municipal General Hospital, Tokyo, Japan. 7. Department of Internal Medicine, Fujimoto General Hospital, Miyakonojo, Japan. 8. Division of Hematology, Tokyo Metropolitan Cancer and Infectious Diseases Centre Komagome Hospital, Tokyo, Japan. 9. Division of Hematology and Oncology, Japanese Red Cross Narita Hospital, Narita, Japan. 10. Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Osaka, Japan. 11. Department of Hematology, Japanese Red Cross Medical Centre, Tokyo, Japan. 12. Division of Blood Transfusion/Division of Medical Oncology and Haematology, Kobe University Hospital, Kobe, Japan. 13. Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Japan. 14. Division of Hematology and Immunology, Otsu Red Cross Hospital, Otsu, Japan. 15. Department of Hematology, Shinko Hospital, Kobe, Japan. 16. Department of Hematology, Shiga Medical Centre for Adults, Moriyama, Japan. 17. Division of Hematology, National Kyushu Cancer Centre, National Hospital Organization, Fukuoka, Japan. 18. Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. 19. Department of Haematology, Teine Keijinkai Hospital, Sapporo, Japan. 20. Division of Haematology, NTT Medical Centre Tokyo, Tokyo, Japan. 21. Division of Haematology, Fujita Health University, Aichi, Japan. 22. Department of Hematology, Hokkaido University Hospital, Sapporo, Japan. 23. Department of Internal Medicine, Hyogo Prefectural Awaji Medical Center, Hyogo, Japan. 24. Department of Hematology, Daiyukai General Hospital, Aichi, Japan. 25. Department of Hematology, Aichi Cancer Center Aichi Hospital, Aichi, Japan. 26. Department of Hematology, Uegahara Hospital, Hyogo, Japan. 27. Department of Hematology, Ogaki Municipal Hospital, Gifu, Japan. 28. Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan. 29. Department of Hematology, National Hospital Organization Osaka-Minami Medical Center, Osaka, Japan. 30. Department of Hematology and Immunology, Kanazawa Medical University Hospital, Ishikawa, Japan. 31. Department of Hematology and Oncology, Kanazawa University Hospital, Ishikawa, Japan. 32. Department of Hematology, Nara Hospital Kinki University, Nara, Japan. 33. Department of Hematology, Imamura Hospital, Kagoshima, Japan. 34. Department of Internal Medicine, Japan Community Health Care Organization, Kobe Central Hospital, Kobe, Japan. 35. Department of Internal Medicine, Shinseikai Toyama Hospital, Toyama, Japan. 36. Department of Hematology, Sumitomo Hospital, Osaka, Japan. 37. Department of Hematology, National Hospital Organization Sendai Medical Center, Sendai, Japan. 38. Department of Hematology, Takarazuka City Hospital, Hyogo, Japan. 39. Department of Hematology and Oncology, Tokai University, Kanagawa, Japan. 40. Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan. 41. Department of Hematology, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan. 42. Department of Transfusion Medicine and Cellular Therapy, Hyogo College of Medicine, Hyogo, Japan. 43. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan. 44. NPO Epidemiological and Clinical Research Information Network (ECRIN), Okazaki, Japan. 45. Division of Hematology, Respiratory Medicine, and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan. Electronic address: shkimu@cc.saga-u.ac.jp.
Abstract
INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.
INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.
Authors: Jerald P Radich; Andreas Hochhaus; Tamás Masszi; Andrzej Hellmann; Jesper Stentoft; María Teresa Gómez Casares; J Valentín García-Gutiérrez; Eibhlin Conneally; Philipp D le Coutre; Norbert Gattermann; Bruno Martino; Susanne Saussele; Francis J Giles; David M Ross; Paola Aimone; Sai Li; Ksenia Titorenko; Giuseppe Saglio Journal: Leukemia Date: 2021-03-11 Impact factor: 12.883